This patent is directed to process control systems and methods, and, in particular, to process control systems and methods for use with filters and filtration processes.
Many products—for example antibodies, and more particularly monoclonal antibodies—are derived from cells. To prepare a cell-derived product, one or more initial unit operations may be performed to remove the cells and any associated cell debris to enable purification. After purification, one or more subsequent unit operations may be performed to prepare the product for administration. Filtration may be included both in the initial and subsequent unit operations, as will be explained below in the context of a general description of the overall process of preparing a cell-derived product.
With reference to commercial-scale unit operations that may be used to prepare a therapeutic-grade extracelluarly-expressed product, such as an antibody or immunoglobulin, an initial separation operation such as centrifugation or filtration may be used to remove cells and cell debris. Centrifugation involves the application of centrifugal force (relative to an axis) to a liquid solution or suspension to cause more-dense components of the solution or suspension to migrate further away from the axis, and less-dense components of the solution or suspension to migrate toward the axis (or at least to migrate less further away from the axis than the more-dense components). Filtration is pressure-driven process that uses membranes to separate components in a liquid solution or suspension according to size differences between the components. When used in a cell separation harvest application, the filtration may be referred to as microfiltration. Either the centrifugation or the filtration referred to above may be preceded by or followed with one or more (additional) filtration unit operations, depending on the amount of cell and/or cell debris initially in the solution or suspension or on the degree to which centrifugation or the primary filtration process has separated out the cells and/or cell debris.
Once the cells and cell debris have been satisfactorily removed, purification may be performed in one or more devices (which may be in the form of one or more columns) using a process known as chromatography. Chromatography involves the interaction between a first phase, referred to as the mobile phase, and a second phase, referred to as the stationary phase. Oftentimes, the product of interest in the mobile phase binds to the stationary phase, and then a solvent (referred to as an eluent) is used to separate the product from the stationary phase. Other times, the product of interest flows through in the mobile phase, while contaminants bind to the stationary phase.
The exact nature of the interaction between the mobile and stationary phases differs with the type of chromatography used. Ion exchange chromatography relies on the forces of attraction between charged molecules of the product of interest (or contaminant) and an oppositely-charged solid phase. For example, in cation exchange chromatography, positively-charged molecules are attracted to a negatively-charged solid phase. Affinity chromatography involves the use of a ligand that specifically binds to the product (i.e., the target molecule) or the contaminant. In regard to an antibody or immunoglobulin product of interest, the ligand may be the associated antigen.
Once purification has been completed, the product that is eluted from the chromatography device may be transported for further processing prior to administration to the patient including for example, formulating the protein in a pharmaceutically acceptable excipient and/or performing filtration. For example, filtration may be performed to remove any viruses present to ensure the virus safety of the biotech-derived therapeutic. Additionally, filtration may be performed on the product to concentrate the product to therapeutic levels and to desalt the product. While the object of the filtration is still to separate larger components from smaller components, unlike the pre-purification filtration performed to remove cell and cell debris from the product, the post-purification filtration removes small peptides and salts from the product so as to increase the concentration of the product. This filtration may also be used to desalt the product, or to introduce a stable drug substance formulation for storage of the product prior to filling (i.e., buffer exchange or replacement). When used in this context, the filtration may be referred to as ultrafiltration.
The filtration described above may be a dead-end process or a crossflow, or tangential flow, process. In a dead-end filter, the flow of the liquid solution or suspension to be separated (or feed) is perpendicular to the membrane. The majority of the feed flow in a crossflow filter is tangential to or across the surface of the membrane.
Tangential flow filtration (or TFF) provides certain advantages to dead-end filtration. In particular, the material that builds up on the membrane surface (also referred to as a stagnant film layer) is minimized during tangential flow filtration, increasing the length of time that a filter can be operational. Consequently, tangential flow filtration may be applied to continuous process applications, in that feed may be continuously fed into and through the filter.
A particular type of tangential flow filtration, referred to as single-pass tangential flow filtration (or SPTFF), may be used in certain applications. While conventional TFF involves directing the feed flow in multiple passes through the filter device (or multiple filter devices arranged in parallel), SPTFF involves directing the feed flow through the filter device in a single pass. According to certain embodiments, the SPTFF filter device may include a single membrane. According to other embodiments, the SPTFF filter device may be defined by a plurality of membrane cassettes connected in series, the retentate of one stage directed into the successive stage as the feed flow. The cassettes may be connected with multiple holders or flow diverter plates. Alternatively, a housing may be designed to receive a plurality of membranes, the housing providing paths for connecting the individual membranes.
As set out in detail below, this disclosure sets forth improved process control systems and methods for filters and filtration, and in particular tangential flow filters and filtration, embodying advantageous alternatives to the conventional devices and methods.